Sipola Joonatan, Munzur Aslı D, Kwan Edmond M, Seo Clara C Y, Hauk Benjamin J, Parekh Karan, Liao Yi Jou Ruby, Bernales Cecily Q, Donnellan Gráinne, Bloise Ingrid, Fung Emily, Ng Sarah W S, Wang Gang, Vandekerkhove Gillian, Nykter Matti, Annala Matti, Maurice-Dror Corinne, Chi Kim N, Herberts Cameron, Wyatt Alexander W, Takeda David Y
Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tays Cancer Center, Tampere University, Tampere, Finland.
Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, British Columbia, Canada.
Cancer Res. 2025 Feb 17;85(4):791-807. doi: 10.1158/0008-5472.CAN-24-2052.
Cell phenotype underlies prostate cancer presentation and treatment resistance and can be regulated by epigenomic features. However, the osteotropic tendency of prostate cancer limits access to metastatic tissue, meaning most prior insights into prostate cancer chromatin biology are from preclinical models that do not fully represent disease complexity. Noninvasive chromatin immunoprecipitation of histones in plasma cell-free DNA (cfDNA) in humans may enable the capture of disparate prostate cancer phenotypes. In this study, we analyzed activating promoter- and enhancer-associated H3K4me2 from cfDNA in metastatic prostate cancer enriched for divergent patterns of metastasis and diverse clinical presentation. H3K4me2 density across prostate cancer genes, accessible chromatin, and lineage-defining transcription factor-binding sites correlated strongly with ctDNA fraction-demonstrating capture of prostate cancer-specific biology and informing the development of a statistical framework to adjust for ctDNA fraction. Chromatin hallmarks mirrored synchronously measured clinicogenomic features: bone- versus liver-predominant disease, serum PSA, biopsy-confirmed histopathologic subtype, and RB1 deletions convergently indicated phenotype segregation along an axis of differential androgen receptor activity and neuroendocrine identity. Detection of lineage switching after sequential progression on systemic therapy in select patients indicates potential use for individualized resistance monitoring. Epigenomic footprints of metastasis-induced normal tissue destruction were evident in bulk cfDNA from two patients. Finally, a public epigenomic resource was generated using a distinct chromatin marker that has not been widely investigated in prostate cancer. These results provide insights into the adaptive molecular landscape of aggressive prostate cancer and endorse plasma cfDNA chromatin profiling as a biomarker source and biological discovery tool. Significance: Plasma cell-free chromatin immunoprecipitation sequencing enables phenotypic dissection of lethal prostate cancer and is a practical tool for biomarker discovery while overcoming prior limitations of access to relevant tissue and reliance on model systems.
细胞表型是前列腺癌呈现和治疗耐药性的基础，且可由表观基因组特征调控。然而，前列腺癌的骨趋向性限制了对转移组织的获取，这意味着此前对前列腺癌染色质生物学的大多数见解都来自不能完全体现疾病复杂性的临床前模型。对人类血浆游离DNA（cfDNA）中的组蛋白进行无创染色质免疫沉淀，可能有助于捕捉不同的前列腺癌表型。在本研究中，我们分析了来自转移性前列腺癌cfDNA中与启动子和增强子相关的激活型H3K4me2，这些转移性前列腺癌具有不同的转移模式和多样的临床表现。前列腺癌基因、可及染色质及谱系定义转录因子结合位点上的H3K4me2密度与循环肿瘤DNA（ctDNA）比例密切相关，这表明可捕捉前列腺癌特异性生物学特征，并为建立针对ctDNA比例进行校正的统计框架提供依据。染色质特征与同步测量的临床基因组特征相互呼应：以骨转移为主与以肝转移为主的疾病、血清前列腺特异抗原（PSA）、活检确诊的组织病理学亚型以及RB1缺失，均一致表明表型沿雄激素受体活性和神经内分泌特征差异轴发生分离。在部分患者接受全身治疗序贯进展后检测到谱系转换，这表明其在个体化耐药监测方面具有潜在用途。两名患者的总体cfDNA中明显存在转移诱导的正常组织破坏的表观基因组印记。最后，利用一种在前列腺癌中尚未得到广泛研究的独特染色质标记物生成了一个公共表观基因组资源。这些结果为侵袭性前列腺癌适应性分子格局提供了见解，并支持将血浆cfDNA染色质分析作为一种生物标志物来源和生物学发现工具。意义：血浆游离染色质免疫沉淀测序能够对致命性前列腺癌进行表型剖析，是一种用于生物标志物发现的实用工具，同时克服了此前获取相关组织的局限性以及对模型系统的依赖。
